'Quadruple helix' DNA discovered in human cells
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Researchers
have shown that four-stranded 'quadruple helix' DNA structures -- known as G- quadruplexes -- exist within the
human genome. (Credit: Jean-Paul Rodriguez and Giulia Biffi)
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In
1953, Cambridge researchers Watson and Crick published a paper describing the
interweaving 'double helix' DNA structure -- the chemical code for all life.
Now, in the year of that scientific landmark's 60th Anniversary, Cambridge
researchers have published a paper proving that four-stranded 'quadruple helix'
DNA structures -- known as G-quadruplexes -- also exist within the human
genome. They form in regions of DNA that are rich in the building block
guanine, usually abbreviated to 'G'.
The findings mark the culmination of over 10 years investigation
by scientists to show these complex structures in vivo -- in living human cells
-- working from the hypothetical, through computational modelling to synthetic
lab experiments and finally the identification in human cancer cells using
fluorescent biomarkers.
The research, published January
20 in Nature
Chemistry and
funded by Cancer Research UK, goes on to show clear links between concentrations
of four-stranded quadruplexes and the process of DNA replication, which is
pivotal to cell division and production.
By targeting quadruplexes with synthetic molecules that trap and
contain these DNA structures -- preventing cells from replicating their DNA and
consequently blocking cell division -- scientists believe it may be possible to
halt the runaway cell proliferation at the root of cancer.
"We are seeing links between trapping the quadruplexes with
molecules and the ability to stop cells dividing, which is hugely
exciting," said Professor Shankar Balasubramanian from the University of
Cambridge's Department of Chemistry and Cambridge Research Institute, whose
group produced the research.
"The research indicates that quadruplexes are more likely
to occur in genes of cells that are rapidly dividing, such as cancer cells. For
us, it strongly supports a new paradigm to be investigated -- using these
four-stranded structures as targets for personalised treatments in the
future."
Physical studies over the last couple of decades had shown that
quadruplex DNA can form in vitro -- in the 'test tube', but the structure was
considered to be a curiosity rather than a feature found in nature. The
researchers now know for the first time that they actually form in the DNA of
human cells.
"This research further highlights the potential for
exploiting these unusual DNA structures to beat cancer -- the next part of this
pipeline is to figure out how to target them in tumour cells," said Dr
Julie Sharp, senior science information manager at Cancer Research UK.
"It's been sixty years since its structure was solved but
work like this shows us that the story of DNA continues to twist and
turn."
The study published January 20 was led by Giulia Biffi, a
researcher in Balasubramaninan's lab at the Cambridge Research Institute.
By building on previous research, Biffi was able to generate
antibody proteins that detect and bind to areas in a human genome rich in
quadruplex-structured DNA, proving their existence in living human cells.
Using fluorescence to mark the antibodies, the researchers could
then identify 'hot spots' for the occurrence of four-stranded DNA -- both where
in the genome and, critically, at what stage of cell division.
While quadruplex DNA is found fairly consistently throughout the
genome of human cells and their division cycles, a marked increase was shown
when the fluorescent staining grew more intense during the 's-phase' -- the
point in a cell cycle where DNA replicates before the cell divides.
Cancers are usually driven by genes called oncogenes that have
mutated to increase DNA replication -- causing cell proliferation to spiral out
of control, and leading to tumour growth.
The increased DNA replication rate in oncogenes leads to an
intensity in the quadruplex structures. This means that potentially damaging
cellular activity can be targeted with synthetic molecules or other forms of
treatments.
"We have found that by trapping the quadruplex DNA with
synthetic molecules we can sequester and stabilise them, providing important
insights into how we might grind cell division to a halt," said
Balasubramanian.
"There is a lot we don't know yet. One thought is that
these quadruplex structures might be a bit of a nuisance during DNA replication
-- like knots or tangles that form.
"Did they evolve for a function? It's a philosophical
question as to whether they are there by design or not -- but they exist and
nature has to deal with them. Maybe by targeting them we are contributing to
the disruption they cause."
The study showed that if an inhibitor is used to block DNA
replication, quadruplex levels go down -- proving the idea that DNA is dynamic,
with structures constantly being formed and unformed.
The researchers also previously found that an overactive gene
with higher levels of Quadruplex DNA is more vulnerable to external
interference.
"The data supports the idea that certain cancer genes can
be usefully interfered with by small molecules designed to bind specific DNA
sequences," said Balasubramanian.
"Many current cancer treatments attack DNA, but it's not
clear what the rules are. We don't even know where in the genome some of them
react -- it can be a scattergun approach.
"The possibility that particular cancer cells harbouring
genes with these motifs can now be targeted, and appear to be more vulnerable
to interference than normal cells, is a thrilling prospect.
"The 'quadruple helix' DNA structure may well be the key to
new ways of selectively inhibiting the proliferation of cancer cells. The
confirmation of its existence in human cells is a real landmark."
Source: University of Cambridge
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